HIV-1 infection remains a major medical problem, with an estimated 42 million people infected worldwide at the end of 2002. The number of cases of HIV and AIDS (acquired immunodeficiency syndrome) has risen rapidly. In 2002, ˜5.0 million new infections were reported, and 3.1 million people died from AIDS. Currently available drugs for the treatment of HIV include, for example, the following nucleoside reverse transcriptase (RT) inhibitors: Retrovir™ zidovudine (or AZT), Videx™ didanosine, Zerit™ stavudine, Epivir™ lamivudine (or 3TC), Hivid™ zalcitabine (or DDC), Ziagen™ abacavir succinate, Viread™ Tenofovir disoproxil fumarate salt, Combivir™ (−3TC plus AZT), Trizivir™ (abacavir, lamivudine, and zidovudine); the following non-nucleoside reverse transcriptase inhibitors: Viramune™ nevirapine, Rescriptor™ delavirdine and Sustiva™ efavirenz, and the following peptidomimetic protease inhibitors: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, Kaletra™ (lopinavir and rtonavir), and Reyataz™ atazanavir sulfate. Often, these drugs can only transiently restrain viral replication if used alone. However, when used in combination, these drugs can have a profound effect on viremia and disease progression. In fact, significant reductions in death rates among AIDS patients have been recently documented as a consequence of the widespread application of combination therapy. However, despite these impressive results, 30 to 50% of patients ultimately fail combination drug therapies. Insufficient drug potency, non-compliance, restricted tissue penetration and drug-specific limitations within certain cell types (e.g. most nucleoside analogs cannot be phosphorylated in resting cells) may account for the incomplete suppression of sensitive viruses. Furthermore, the high replication rate and rapid turnover of HIV-1 combined with the frequent incorporation of mutations, leads to the appearance of drug-resistant variants and treatment failures when sub-optimal drug concentrations are present. Therefore, novel anti-HIV agents exhibiting distinct resistance patterns, and favorable pharmacokinetic as well as safety profiles are needed to provide more treatment options whether used alone or in combination with other drugs.
HIV expresses three enzymes, reverse transcriptase, an aspartyl protease and integrase, all of which are potential antiviral targets for the development of drugs for the treatment of AIDS. However, integrase stands out as being the only viral enzyme not targeted by currently approved therapy. The integrase enzyme is responsible for insertion of the viral cDNA into the host cell genome, which is a critical step in the viral life cycle. There are a number of discrete steps involved in this process including processing of the viral cDNA by removal of two bases from each 3′-terminus and joining of the recessed ends to the host DNA. Studies have shown that in the absence of a functional integrase enzyme HIV is not infectious. Therefore, an inhibitor of integrase would be useful as a therapy for AIDS and HIV infection.
A number of HIV integrase inhibitors have been reported. These include nucleotide-based inhibitors, known DNA binders, catechols and hydrazide containing derivatives (Neamati, N.; Sunder, S.; Pommier, Y., Drug Disc. Today, 1997, 2, 487).
Certain pyrimidines and pyrimidinones have been disclosed. WO 02/06246 discloses 2-aryl-4,5-dihydroxy-6-carboxypyrimidines as viral polymerase inhibitors which are proposed for use in treating hepatitis C virus infection. Sunderland, C. J; Botta, M.; Aime, S.; and Raymond, K. N. Inorg. Chem. (2001) 40, 6746–6756 discloses the synthesis of 6-carboxamido-5,4-hydroxypyrimidinones as gadolinium chelating agents.